I started out in an Engineering program at a Canadian University a couple years ago. Shortly thereafter I decided I wanted to be a programmer. Totally reasonable life choices, that came with some slightly less reasonable time demands.

You see when you’re in an engineering program pulling all-nighters to get work done start becoming fairly normal. And then if you want to become a programmer you now need to digest thousands of lines of documentation and code, which definitely doesn’t help you get all the schoolwork done in a nice timely manner. And then we compound that with the recent phenomenon of hackathons. Hackathons are 24-48hr long programming meetups where you, alone or in a team, write code hoping to create something interesting, like a mobile app, or program. As it currently stands, getting employed at a top tier tech firm is nigh nearly impossible for an undergraduate student without hackathon experience.

So this led me to try and find some way to make it easier for myself to stay awake, and get work done. University students are often familiar with ADHD medication of some sort or the other. These include Ritalin, Adderall, Vyvanse, Biphentin and many others. But they’re only so effective and have some undesirable side effects. But hey, I’m not trying to tell you to not take drugs here, drugs are bad, you know this from the millions of dollars spent by many governments vilifying them under one undiscriminating umbrella term. No, I’m going to teach you how to intelligently use drugs to get the results you desire.

A brief primer on the brain

Hackathons are great learning experiences, you get to try new frameworks and tools with minimal risk. You see, to build something in programming, you need to understand the tools and solutions that exist in that space. To engineer a better bridge, you need to understand how bridges work and are built. So we need to understand the human brain a little bit.

Most of you should know that a human brain is a biological electrochemical system consisting of cells called neurons. Neurons connect to each other and basically store you. Who you are, your memories, your ability to add numbers, everything is stored as connections in a dense mesh of cells in your cranium. Neurons communicate via signals triggered by electrical charges that cause chemical messengers to be released into a tiny gap in between them and accepted by another neuron on the other side. So to hack it, we will either have to use electromagnetic phenomenon or chemicals.

Although transcranial direct current stimulation has been noted to positively influence wakefulness [1] wearing a magnet and electrical equipment on my head doesn’t seem too attractive so instead let us enter the wonderful world of neuropsychopharmacology.

Right so about those chemical messengers. Well, they’re called neurotransmitters. There’s oh so many of them. Their release is usually mediated by voltage differentials in the neuron itself (keep this in mind, it’ll come up later). The place where two neurons connect is called a synapse, and there’s a tiny gap between them. After crossing the tiny gap, which is also called the synaptic cleft, these little guys fall into receptor sites. Think of it as a jigsaw puzzle, a specific shape of receptor goes with a specific shape of neurotransmitter. But there are man-made chemicals as well that can fit into the receptor and cause interesting effects since they have somewhat similar shapes to the neurotransmitters. Not all these neurotransmitters lock into receptors, some are sucked back into the neurons via recovery vents. This is called reuptake.

The neurons also have some receptors along their bodies, which allow them to judge and react to the environment. For example slowing down if the environment tells them the person is tired or trying to go to sleep. Though these aren’t actively used to send messages along.

Well now we know a bit about the brain but what about sleep? Sleep has a myriad of purposes, so I do not recommend long periods of severe sleep deprivation. These include muscle recovery and repair. Formation of long-term memories. The brain also does housekeeping and maintenance, flushing out by-products of cellular function and rearranging neuron formations.[2] At the end of the day, sleep is necessary, but that doesn’t mean we can’t engineer around having to sleep every night. But not sleeping at all for an extended period can have dire consequences, even death.

Wakefulness and receptors

Well, there are 3 main receptor types that I’ve identified that have something to do with wakefulness. Since many chemicals can affect the same receptor and the receptors often have subtypes these 3 receptor types provide a nice framework to reason about hacking sleep and chemical targets. I came to this hypothesis by looking at the mechanisms of actions of a plethora of drugs which are known to affect wakefulness.

These are the adrenergic, dopaminergic and adenosine receptors. But I should mention that sleep is complex, so is the human brain, and other neurotransmitters like serotonin and glutamate also play a part. For a purely curious mind I recommend reading “Neuropharmacology of sleep” on NCBI.

Dopamine receptors

Ah yes dopamine, many of you have probably heard of it. It is responsible for reward-motivated behavior. If you study hard and get those grades for yourself and it makes you feel good, well it’s the dopamine. Too much dopamine and you’ll be lazy and not want to do anything, too little and you’ll get bored, yawn, maybe fall asleep(anyone else have 8 am engineering lectures?). It plays a very real role in sleep.[3][4]

You will usually have too little dopamine trying to pull all-nighters. We’ll be looking at drugs that increase dopamine concentrations in the brain and supplements that are easily metabolized to it to prevent depletion. You also want to block its reuptake to maximize signaling strength. Dopamine reuptake inhibitors, precursors or anything that increases dopamine transporter activity causing it to release more is your friend.

Adenosine receptors

Fewer people have probably heard of this one, but almost all of you have exploited this poor guy in the past. Ever drink coffee? Green tea? Energy drinks? This is the main target for all of those.

You see as you get sleepier, this pesky little molecule called adenosine builds up in your brain as a breakdown product of ATP (your cells generate energy via the ATP->ADP reaction). It binds to its namesake receptor, which in turn triggers some very calming effects like slowed heart rate, reduction in dopaminergic signalling, muscle relaxation etc. All effects we don’t want. So we drink coffee, which blocks these receptors, preventing adenosine in our brain from getting in and triggering its effects. So what you need are adenosine antagonists.

Adrenergic receptors

These guys are responsible for triggering your adrenal system. The whole fight or flight response. If you overstimulate them well you’ll be panicky, anxious, paranoid your heart will explode from the excessive beating. But a small amount can do wonders for alertness and wakefulness. One should note that drugs that target the dopamine and adrenergic receptors can sometimes be found under the category of monoaminergics on online retail sites.

Drugs

Alright, time for the fun stuff. I didn’t just almost put you to sleep droning on about receptors and what-not for nothing. Time to teach you how to hack around the biological need for regular sleep. I can’t talk about all the drugs since new ones come out pretty often, but you can identify drugs that’ll work based on the receptors and underlying systems they target. For the best results, we want drugs that have different mechanisms of actions on these systems stacked together.

Amphetamines

Remember those drugs kids at school take we talked about earlier? Adderall etc. They’re amphetamines or amphetamine derivatives, all of them, and share similar mechanisms of actions. They work mainly on the dopamine and adrenaline systems.

By increasing DAT (dopamine transporter) activity, they cause your neurons to dump more dopamine into the presynaptic cleft. It works in the same way on the adrenergic system and also triggers similar effects on a myriad of other neurotransmitters like acetylcholine, glutamate, and serotonin. But there are other drugs that can be acquired cheaper and without legal restrictions which have the same mode of action. They can often be found in supplements for weight lifting as stimulants or pre-workouts.

For example one drug that is rather easy to get at bodybuilding and supplement stores is Ephedrine. It’s similar to amphetamine in structure and affects the dopaminergic and adrenergic systems just like the most popular ADHD medication. It doesn’t work quite as well, though.

But these amphetamine derivatives also have a dark side.

First off if you take too much your neurons will fry themselves. Remember how I mentioned neurotransmitter based transmission is triggered by electric currents in the cells? When a super excited neuron dumps a ton of dopamine, the tiny electric charge causing it is enough to damage it, permanently. But then it cascades, and the next neuron in queue attempts to pass on the signal, frying itself in the process and so on and on. Don’t worry, there’s millions of them, or actually do worry a little bit. Neurons are easily excited, and like a very very old man with a myriad of health problems, too much excitement can and does kill it.[5]

Secondly, regular use of ADHD medication can and does cause a dependency. So you’ve effectively given yourself ADHD and can’t really function without it.[6]

Third, amphetamine use severely drains your neurotransmitters. You need to replenish them. Keep reading and I’ll tell you how. They also cause stress and fatigue in the underlying systems, namely the adrenergic and dopaminergic systems and to a lesser extent the serotonergic system. So if you feel burnt out afterwards, try taking half the dose or less the next time. a 10% constant boost is better than a 20% boost followed by a 80% degradation.

The brotherhood of Modafinil

Now let’s consider a slightly more exotic drug. Modafinil. This guy been around for a long time and the militaries around the world love it. I just found out my home nations (India) air force includes it in contingency plans. Brilliant! Soldiers that don’t need to sleep. Now if only they could find planes that didn’t fall out of the sky on a regular basis.[7]

Modafinil works via the dopaminergic and adrenergic systems.[8] It works as a dopamine reuptake inhibitor, which means stronger signals due to more dopamine in the presynaptic cleft, and it increases norepinephrine levels in the synaptic cleft in a similar way to amphetamines.

An important factor to keep in mind is that it’s a low-affinity binder, which means:

It works slowly (expect 2 hrs)

Its mild (you won’t necessarily feel it, but trust me, when it’s 4am and you look around and everyone but you is yawning, you’ll know it worked)

Adrafinil

This guy gets metabolized to modafinil in the liver. A strange queasiness might be felt in the liver as the enzyme activity increases. Not as effective as modafinil since a lot of it is destroyed in the metabolic process.

Hydrafinil

Some people absolutely love this stuff. The name is a marketing play and the molecule itself doesn’t have much in common with modafinil.[9] Though common criticisms are that it looks funny, clumps easily, has a very short duration of effect and it’s as effective as Modafinil.

Flmodafinil

AKA CRL-409,40 (or Bisfluoromodafinil), current heavyweight champion of the modafinil alternatives world. Basically modafinil with two fluorine atoms added to it. This increases the bio-availability of the drug by increasing its lipophilicity (it crosses the blood brain barrier easier since it’s more fat soluble)[10]

Recommended dose is 50-100 mg, up to 200mg if you plan on staying up for 48hrs.

Fladrafinil

AKA CRL-409,41 (or Bisfluoroadrafinil) I recommend you do not take this. It’s basically adrafinil with two fluorine molecules and all anecdotal reports say it doesn’t work very well. If you do try it, write to us and tell us how it went!

Modafinil and it’s derivatives is a lot safer than amphetamines and stimulants like Adderall, but still don’t take a massive dose. I can tell you from personal experience that staying awake for 3 days in a row isn’t fun.

Good ol’ cuppa joe

So far we’ve targeted the dopaminergic and adrenergic systems. Let’s look at adenosine real quick. Your best bet (and cheapest) is to simply drink a cup of coffee. Many in the nootropics community love a little bit of l-theanine with their coffee, feel free to try that if coffee makes you too jittery.

But don’t drink too much coffee. It’ll backfire. If you drink large amounts of coffee continuously, your brain reacts by upregulating adenosine receptors on the neuron heads and by increasing the amount of adenosine in your brain, and this causes you to be constantly sleepy, tired and to need coffee to barely function. If you’re at a hackathon, hold up on the coffee till it’s near the end and you absolutely can’t function without it.

I found myself continuously getting addicted to coffee, requiring it to just stay awake and then going through a painful withdrawal/cleanse, so I switched to green tea. There are more powerful and targeted adenosine receptor blockers though they aren’t very well known or easily found. These belong to the Xanthine family of molecules. Write to us if you have any hands on experience with them, we’d love to interview you.

Recovery

“But I feel like shit after pulling all-nighters or going to hackathons!”

Well duh, what’d you expect to feel like? A million bucks?

Here’s what happened, your brain depleted a ton of its neurotransmitters thinking your thoughts. Energy stores are also depleted. I highly recommend taking a dopamine precursor afterward or even as part of your drug stack.

N-Acetyl-L-Tyrosine, better known as NALT, is a crowd-pleaser in that category. The main part of those four letters is the T, and it stands for tyrosine. Tyrosine is an amino acid that is readily metabolized to dopamine. Dopamine is further metabolized to norepinephrine which you depleted stressing your adrenergic system. Bam! Two birds, one stone. Mice treated to have extra dopamine also have a stronger reaction to modafinil and caffeine and ended up recovering better from sleep deprivation than untreated mice.[11]

So what about the adenosine we blocked? Well, there isn’t much you can do about that. Take a nap, even if it’s a quick 10-30-minute nap or you just close your eyes and think about stuff during your waking stint. It’ll flush some of the adenosine out of your brain. It’ll also help you get over writers block if you feel incredibly fatigued before you can afford to sleep properly.

And finally, eat something, even if you’re not hungry from all the stims in your body. I’m not going to go into dieting and what proper foods are. But hopefully, you know this part.

Best of luck with your endeavors, whatever they may be. And remember I’m not a doctor and even if I was, you take advice from a stranger on the internet at your own risk.